CYP19A1 Variation in Healthy Children: Associations with Breast Development and Pubertal Gynecomastia
Veronica L. R. Groendahl, Stine A. Holmboe, Alexander S. Busch, Casper P. Hagen, Jørgen H. Petersen, Trine H. Johannsen, Kristian Almstrup, Hanne Frederiksen, Anders Juul, Lise AksglaedeAbstract
Background
CYP19A1 encodes aromatase, the enzyme converting androgens to estrogens, thereby influencing breast tissue development in healthy children.
Objective
To examine associations between CYP19A1 single nucleotide polymorphisms (SNPs) and circulating estradiol (E2), testosterone (T), the E2/T ratio, and age at thelarche in girls, and presence of gynecomastia in boys.
Methods
A total of 1023 healthy participants (aged 5.9-20.0 years) from the Copenhagen Puberty Study were assessed for pubertal status and serum sex steroid concentrations were measured by LC-MS/MS. Genotyping of CYP19A1 SNPs (rs727479 A>C, rs2899472 A>C, rs10046 C>T) was performed.
Results
Girls with AA genotype in rs727479 and rs2899472 showed tendencies toward earlier pubertal onset. In a combined efficacy-allele model, each additional allele was associated with 1.6 months earlier puberty (p = 0.06), and girls with 5-6 vs. 0-2 efficacy alleles presented with significantly lower pubertal age (p = 0.02). CYP19A1 genotype was not associated with E2, T, or E2/T levels. Boys with CC genotype in rs727479 had the highest prevalence of pubertal gynecomastia (73%, p < 0.01). Boys with gynecomastia showed higher E2 and T (SDS) than unaffected boys (both p < 0.01), with no difference in E2/T. In age-matched analyses, E2 (SDS) remained elevated in boys with gynecomastia (0.81 vs. 0.19, p = 0.04).
Conclusion
CYP19A1 variants may influence pubertal timing in girls. In boys, pubertal gynecomastia appeared to be linked with CYP19A1 genotype and was associated with elevated E2 concentrations.
Significance statement
Aromatase, encoded by CYP19A1, catalyzes the conversion of androgens to estrogens. The contribution of common CYP19A1 genetic variants to variation in pubertal development in healthy children is not fully understood. In this cohort from the Copenhagen Puberty Study, we examined associations between CYP19A1 polymorphisms, circulating sex steroid concentrations, age at puberty and pubertal gynecomastia in boys. By integrating genetic, hormonal, and clinical pubertal data, this study provides additional insight into potential links between aromatase-related genetic variation and normal pubertal development.